The Definitive Guide To Autophagy (and 7 Ways To Induce It)

Biological systems are self-maintaining. They have to be. We don’t have maintenance workers, mechanics, troubleshooters that can “take a look inside” and make sure everything’s running smoothly. Doctors perform a kind of biological maintenance, but even they are working blind from the outside.

No, for life to sustain itself, it has to perform automatic maintenance work on its cells, tissues, organs, and biological processes. One of the most important types of biological maintenance is a process called autophagy.

Autophagy: the word comes from the Greek for “self-eating,” and that’s a very accurate description: Autophagy is when a cell consumes the parts of itself that are damaged or malfunctioning. Lysosomes—members of the innate immune system that also degrade pathogens—degrade the damaged cellular material, making it available for energy and other metabolites. It’s cellular pruning, and it’s an important part of staving off the worst parts of the aging process.

In study after study, we find that impairment to or reductions of normal levels of autophagy are linked to almost every age-related degenerative disease and malady you can imagine.

Cancer: Autophagy can inhibit the establishment of cancer by removing malfunctioning cellular material before it becomes problematic. Once cancer is established, however, autophagy can enhance tumor growth.

Humans traditionally and historically lived in a very different food environment. Traditionally and historically, humans were feasters and fasters. While I don’t think our paleolithic ancestors were miserable, wretched, perpetually starving creatures scuttling from one rare meal to the next—the fossil records show incredibly robust remains, with powerful bones and healthy teeth and little sign of nutritional deficits—they also couldn’t stroll down to the local Whole Foods for a cart full of ingredients. Going without food from time to time was a fundamental aspect of human ancestral life.

They worked for their food. I don’t mean “sat in a cubicle to get a paycheck to spend on groceries.” I mean they expended calories to obtain food. They hunted—and sometimes came back empty handed. They dug and climbed and rooted around and gathered. They walked, ran, stalked, jumped, lifted. Movement was a necessity.

In short, they experienced energy deficits on a regular basis. And energy deficits, particularly sustained energy deficits, are the primary triggers for autophagy. Without energy deficits, you remain in fed mode and never quite hit the fasted mode required for autophagy.

Now compare that ancestral food environment to the modern food environment:

Almost no one goes hungry. Food is cheap and plentiful, with the tastiest and most calorie-rich stuff tending to be the cheapest and most widely available.

Few people have to physically work for their food. We drive to the store and walk a couple hundred steps, hand over some money, and—BOOM—obtain thirty thousand calories, just like that. Or someone comes to our house and delivers the food directly.

We eat all the time. Unless you set out to do it, chances are you’ll be grazing, snacking, and nibbling throughout the day. We’re in a perpetually fed state.

The average person in a modern society eating a modern industrial diet rarely goes long enough without eating something to trigger autophagy. Nor are they expending enough energy to create an energy deficit from the other end—the output. It’s understandable. If our ancestors were thrust into our current situation, many would fall all over themselves to take advantage of the modern food environment. But that doesn’t make it desirable, or good for you. It just means that figuring out how to trigger autophagy becomes that much more vital for modern humans.

Here are 7 ways to induce autophagy with regular lifestyle choices.

1) Fast

There’s no better way to quickly and reliably induce a large energy deficit than not eating anything at all. There are no definitive studies identifying “optimal” fasting guidelines for autophagy in humans. Longer fasts probably allow deeper levels of autophagy, but shorter fasts are no slouch.

2) Get Keto-Adapted

When you’re keto- and fat-adapted, it takes you less time to hit serious autophagy upon commencing a fast. You’re already halfway there.

3) Train Regularly

With exercise-related autophagy, the biggest effects are seen with lifelong training, not acute. In mice, for example, the mice who are subjected to lifelong exercise see the most autophagy-related benefits. In people, those who have played soccer (football) for their entire lives have far more autophagy-related markers of gene activity than people of the same age who have not trained their whole lives.

7) Consume Extra Virgin Olive Oil

Disclaimer: The autophagy/nutrient literature is anything but definitive. Most studies take place in test tube settings, not living humans. Eating some turmeric probably won’t flip a switch and trigger autophagy right away, but it won’t hurt.

Autophagy is a long game.

This can’t be underscored enough: Autophagy is a lifelong pursuit attained by regular doses of exercise and not overeating every time you sit down to a meal. Staying so ketotic your pee tests look like a Prince album cover, doing epic 7-day fasts every month, fasting every other day, making sure you end every day with fully depleted liver glycogen—while these strategies might be “effective,” obsessing over their measures to hit some “optimal” level of constant autophagy isn’t the point and is likely to activate or trigger neurotic behavior.

Besides, we don’t know what “optimal autophagy” looks like. Autophagy isn’t easy to measure in live humans. You can’t order an “autophagy test” from your doc. We don’t even know if more autophagy is necessarily better. There’s the fact that unchecked autophagy can actually increase existing cancer in some cases. There’s the fact that too much autophagy in the wrong place might be bad. We just don’t know very much. Autophagy is important. It’s good to have some happening. That’s what we have to go on.

Putting These Tips Into Practice

Autophagy happens largely when you just live a healthy lifestyle. Get some exercise and daily activity. Go hard every now and then. Sleep deeply. Recover well. Don’t eat carbohydrates you don’t need and haven’t earned (and I don’t just mean “earned through glycogen depleting-exercise”). Reach ketosis sometimes. Don’t eat more food than you need. Drink coffee, even decaf.

All those caveats aside, I see the utility in doing a big “autophagy session” a few times a year. Here’s how mine looks:

Do a big training session incorporating strength training and sprints. Lots of intense bursts. This will trigger autophagy.

Fast for two or three days. This will push autophagy even further.

Stay busy throughout the fast. Take as many walks as possible. This will really ramp up the fat burning and get you quickly into ketosis, another autophagy trigger.

Drink coffee throughout the fast. Coffee is a nice boost to autophagy. Decaf is fine.

I know people are often skeptical of using “Grok logic,” but it’s likely that most human ancestors experienced similar “perfect storms” of deprivation-induced autophagy on occasion throughout the year. You track an animal for a couple days and come up short, or it takes that long to make the kill. You nibble on various stimulants plucked from the land along the way. You walk a ton and sprint some, then lift heavy. And finally, maybe, you get to eat.

If you find yourself aging well, you’re on the right track. If you’re not progressing from obesity to diabetes, you’re good to go. If you’re maintaining and even building your muscle despite qualifying for the blue plate special, you’ve probably dipping into the autophagy pathway. If you’re thinking clearly, I wouldn’t worry. Obviously, we can’t really see what’s happening on the inside. But if everything you can verify is going well, keep it up.

That’s it for today, folks. If you have any more questions about autophagy, leave them down below and I’ll try to get to all of them in future posts.

About the Author

Mark Sisson is the founder of Mark’s Daily Apple, godfather to the Primal food and lifestyle movement, and the New York Times bestselling author of The Keto Reset Diet. His latest book is Keto for Life, where he discusses how he combines the keto diet with a Primal lifestyle for optimal health and longevity. Mark is the author of numerous other books as well, including The Primal Blueprint, which was credited with turbocharging the growth of the primal/paleo movement back in 2009. After spending three decades researching and educating folks on why food is the key component to achieving and maintaining optimal wellness, Mark launched Primal Kitchen, a real-food company that creates Primal/paleo, keto, and Whole30-friendly kitchen staples.

While we await a reply from Mark, one of the confusing things about autophagy is that cancers actually use autophagy as a survival mechanism within the tumor itself , however my understanding is that that is completely different from the autophagy that is being discussed here which is related to non-cancerous cells. Also, the actions in the post likely have numerous anti-cancer affects beyond just autophagy (not to be confused with apoptosis, which is programmed cell death.) Further, once a cancer is established, if you tried to stop autophagy to fight the cancer it would not work since the cancer overrides outside inputs, just like it can keep mTOR upregulated independent of the rest of the body.

I think a further in-depth look at authophagy for cancer survivors would be helpful. I understand from this that it is not recommended when a tumor is present, but what if you do not have any evidence of remaining cancer cells?

How would you know if you had the beginnings of cancer and that you were not promoting it through autophagy? This is the scary part for me. Could we put ourselves into a situation where cells that may have been killed off by the body’s own immune system (apoptosis) instead are enhanced through autophagy?

Autophagy has different impacts on cancers, depending on the specific type of cancer you have, the location of the cancer in the body and the staging. I used extended fasting (autophagy) to reduce the size of my tumor and to enhance the effects of my chemo and radiation therapies. It worked very well for my particular case, my treatment side effects were much reduced, my cancer was cured quickly and my quick and complete recovery has impressed all three of my oncologists. However, while studying before treatment to determine the best course of action for me in my case, I learned that while autophagy and fasting was very helpful for my particular case, it was shown to be detrimental for other types of cancer or other locations of cancer.

I would love to fast but am currently trying to gain weight. Eating lots of grass-fed meats and nuts is slowly helping. (Not a fan of avacadoes and sweet potatoes.) What advice can you give me per staying keto and gaining weight with or without fasting.

@Ellison Garvin Weist. Intermittent fasting improves autophagy, and you only need to need to fast for a minimum of 12 hours each day.

To gain weight, it helps to add chocolate to the nuts. I get Trader Joe’s Absolute 100% Black chocolate, which doesn’t contain dairy, sugars, or soy. If you can consume sugar, then there are chocolates you can get that are made with raw coconut sugar is also good, no dairy and no soy.

For me, gaining weight without either carbs or dairy is HARD. So if you can tolerate the lactose and casein I think that cheese & heavy cream would be your best bet (just put them on or in *everything*). If not, you’re going to have a much more difficult time.

If you’re just trying to bulk for muscle-building purposes, I’d say look into trying to sneak more calories into the foods you already eat. Give your veggies a nice pool of butter (or ghee or whatever oil you like) to swim in. Crush nuts and use them to “bread” your chicken/fish. Eat nut butters instead of whole nuts (you will naturally eat more this way). Go crazy with keto-approved condiments and sauces. Eggs, especially the yolks, are good if you tolerate them, plus they are the base of some great high-fat sauces (mayonnaise, hollandaise, etc). Did you know mayonnaise was originally a steak sauce? Pesto is best known as a pasta sauce but is delicious on steak, chicken, salmon.. slather it on anything, really. Finally, get fatty cuts of meat and eat everything you can chew enough to swallow safely (a little gristle never hurt anyone!). If you find yourself getting physically repulsed by a food bc it’s so fatty, try adding extra salt. It will make the fat more palatable so you can eat more of it IME.

If you need to gain weight for health reasons, a keto diet might not be the best choice for right now. You can still intermittent fast, though, as long as you’re getting enough calories in during your feeding window. This will get easier with practice as your stomach becomes accustomed to eating large amounts of food in one sitting. To really boost weight gain, liquified foods are your friends (not soups, which are mostly water, but solid foods that are puréed/blended). When I got dangerously thin due to GI absorption issues, I would drink two smoothies a day with the following ingredients: 1 cup frozen berries, 1 cup heavy cream or coconut milk/cream, 1/2 of a dark chocolate bar, 1/2 cup nut butter, 1/4 cup coconut oil or mct oil. Altogether this is about 1900-2400 calories, 180-240g fat, 35g protein, 60-65 carbs. Sometimes I’d add other things to sweeten it and up the carbs, like a banana or a tablespoon of honey or some dried fruit. You could add protein powder too if you wanted. It turns out very thick and kind of chunky but it’s packed with calories and goes down super easy. I’d also suggest you find a staple carb that won’t make you feel ill (white rice and white potatoes work for me, but everyone’s different) and eat about a cup of it a day, saturated in your fat of choice.

I can’t eat a lot of things, because of digestive issues. Some of the foods I have to try to maintain my weight include extra virgin olive oil (that’s high in healthy fats and calories), organic whole milk, butter instead of margarine, and concord grape juice.

Please check and make sure that any illnesses that can cause a failure to absorb nutrition aren’t present. If you are an undiagnosed Celiac, then just casually avoiding gluten won’t work since the autoimmune reaction will affect multiple organs for you, plus the gut. But there are other reasons you might not gain weight so I just wanted to throw that out there, because a diet should not be a substitute for medical diagnosis.

You can certainly gain weight on a keto diet easily by eating too much fat. Just like eating too much carb, except it takes much less because 1 g of fat = 9 calories VS 1g carb = 4 calories. So focus on more “fat bombs” and weight training with a little extra protein to support it if it’s intense.

My local Vitamin Shoppe now has a sign saying they’re the local Keto headquarters so check into your local one and ask for more personal advice there, but don’t sub it for medical care if you need it. Not being able to keep weight on is a pretty serious thing and its cause should be looked into.

I want to be sure I understand your autophagy session correctly. Would this sample two day session follow the guidelines?
1. Wake up Saturday morning, drink black coffee/ water only
2. Do a big training session incorporating strength training and sprints
3. Fast throughout the rest of the day
4. Walk throughout the rest of the day
5. Wake up Sunday morning, drink black coffee and water
6. Fast throughout the day
7. Walk throughout the day

I wondered that too. There might be something specific in coffee that triggers autophagy, but I’ll have to skip it if there is. Coffee gives me too many GI problems.

Truth be known, I think aging well is mostly hereditary. The only thing listed here that I do regularly is IF for 16 to 18 hours most days, meaning I eat dinner early and skip breakfast. I seem to be aging very well with no health issues (knock on wood). But whether that helps or not, I couldn’t say. It’s just a normal eating pattern for me.

Thanks, Mark great list. I believe heat exposure such as sitting in a sauna and cold exposure (cold shower etc.) is a pretty powerful inducer of autophagy. As far as supplementation goes, quercetin is proported to be good for mitigating cell senescence.

Interesting. As a cancer survivor, I found fasting during recovery very helpful. It made me feel better. Chemo killed my sense of taste so fasting was easy. After 4 months of oral chemo (Xeloda) I was declared cancer-free. It would be nice to say fasting was a key to my success, but I am not totally convinced.

Cancer loves glucose from any source. Fasting reduces the amount of glucose. But does fasting really do enough to starve cancer cells?

Fasting, for 16-24 hrs before chemo, causes your healthy cells to ‘protect’ themselves. The has the double effect of helping you recover from the chemo while directing the chemo effect towards the desired cancer cells so I would say the research is starting to show that what you did is beneficial in fighting cancer while using chemo.

Great article Mark, very informative. Quick question though – I was under the impression that one only had to avoid carbs and proteins in order to activate authophagy? On my ‘fasting’ mornings I consume spinach in olive oil, turmeric and apple cider vinegar, together with some mushrooms. Sometimes with some capers thrown in (very high in quercetin which should boost authophagy).Shouldn’t that be just as good (if not better than) ‘pure’ fasting – except without the hunger? Works for me anyway…

I am taking a senolytic activator combining black tea theaflavins with an ultra-absorbable form of quercetin. This is supposed to attack senescent cells. Senolytic activators do slow down aging but they have been impractical. This formula is quite inexpensive and safe.

I’ve encorporated autophagy as part of my long-term Traumatic Brain Injury healing for over a decade now, and have slowly and steadily improved (with oh so much further to go!). Here is a post I shared on it linking back to this great guide. Thank you, Mark, for bringing these resources and understandings together! https://mindyourheadcoop.org/help-your-brain-heal-by-your-body-eating-itself

There is some truth in the phrase “don’t eat so close to bedtime”? I always slept better when I went to bed right after dinner, especially now that I’m carnivore and have no symptoms of GERD (wich I have had sometimes even eating paleo/primal and or keto before).

I think that autophagy regimen sounds brutal.
I wonder how teas would compare to coffee here, decaf compared to regular, caffeine vs theobromine.
I was interested in yerba mate due to its theobromine content since reading about it and recently got some and some other teas from a food bank, mostly organic (score!). The first ingredient is a lemon something (verbana I think) but yerba is second or high on the list and it’s a tasty tea that seems to do what theobromine is supposed to: vitalize you without leaving you as jittery as something with more caffeine would. Green tea and chocolate are other good sources of theobromine; in its effects yerba is kind of comparable to green tea.
More on the taste: it’s kind of like Fruit Loops. I think if you steeped lemon verbana and bergamot you’d really have a Fruit Loop – tasting tea. I think they might use bergamot extract as an ingredient.
Other teas I got include green ginger and a turmeric + cinnamon + ginger, both good. Maybe ginger would help regulate autophagy, or as spell check recommends, “autograph”.

I had estrogen-dominateds breast cancer five years ago. Fasting got me through chemo (I followed the protocol of Valter Longo during treatment), operations and radations, and I stayed fit. I hardly experienced any side effects. I have been cancer free for 5 years now. I have done IF for a couple years now, and I love it. Reading this, I wonder if it is wise for me to induce (more) autophagy. I will not go for the autophagy sessions described here though.

Thank you Mark…this was so helpful! I really struggle with fasting, and just do it when it seems to happen naturally. However, I’m doing pretty much everything else on the list. Giant yes to coffee, turmeric and EVOO. They are all a big part of my life. And I’m definitely fat adapted. And it’s probably just as well that autophagy can’t be measured very well. Because then we’d all be making ourselves crazy. At 52 I consider myself to be aging very well so I’ll take it as a sign that autophagy is working for me.

It makes great sense to me that anything that involves stressing your body systems would be problematic if you already have an illness causing stress. And it sounds pretty clear that autophagy is initiated by various types of stress.

I would love to see research on fasting for people with a high risk for cancer due to genetic cancer syndromes. I am a previvor (have not been diagnosed with cancer) but am at high risk for many cancers. I wonder if fasting would be protective and preventive OR if my risk for cancer means it would give fuel to potentially existing but unknown cancers causing them to grow faster than they otherwise would.

With the statement “Autophagy isn’t easy to measure in live humans.(and I will go so far as to say it’s not) … We don’t even know if more autophagy is necessarily better.” and then end with “Autophagy is important. It’s good to have some happening. That’s what we have to go on.” is absolutely ridiculous! How can you say it’s good to have some going on when we don’t know what’s going on? I am in favor of exercise, eating real food and fasting to some extent because we have measured that there are good outcomes for a lot of people, but let’s not all jump on the autophagy bandwagon because it happens to be the latest thing. When science can show a real measurable benefit I will, but not until because we really don’t know what we’re talking about.

What I always enjoy about these articles are that they contain suggestions that’s are relatively simple, and very practical. Read some of the comments, and you are back into very technical approaches to health that seem much more involved and technical.

Did I read this above sentence correctly?
“Once cancer is established, however, autophagy can enhance tumor growth.”
Does that mean that anyone with Cancer shouldn’t intermittent fast or anything else causing autophagy?